1. Field of the Invention
The present invention relates to Enigma (PDLIM7)-Mdm2 interaction and use thereof, more particularly, to a method of treating cancer using interaction between Enigma (PDLIM7) and Mdm2, and regulation of Enigma expression, and an anti-cancer agent.
2. Description of the Related Art
The tumor suppressor p53, which regulates the genes associated with cell growth arrest and apoptosis, has been known as an essential factor preventing normal cells from becoming cancerous cells by removing abnormal cells (Michael and Oren, Cncer Biol., 13, 49-58, 2003). This function of p53 is very strictly regulated for the survival of normal cells, and Hdm2/Mdm2 (human/mouse double minute 2; hereinafter referred to as “Mdm2”) plays a main role in the regulation. The Mdm2, which is an E3 ubiquitin ligase that ubquiquinates p53 for degradation, regulates protein level of p53 in the cell (Haupt et al., Nature, 387, 296-299, 1997; Honda et al., FEBS Lett., 420,25-27,1997). Furthermore, Mdm2 forms an autoregulatory loop where the Mdm2 expression is regulated by the transcriptional control of p53 (Michael and Oren, Cancer Biol., 13, 49-58, 2003). Also, the Mdm2 ubiquitinates Mdm2 itself for degradation (Fang et al., J. Biol. Chem., 275, 8945-8951, 2000; Honda and Yasuda, Oncogene, 19, 4173-4176, 2000).
The Mdm2 deactivates p53 or acts p53-independently as an oncogene and is actually overexpressed throughout various human cancer tissues (Onel, K & Cordon-Cardo, C. Mol Cancer Res 2, 1-8, 2004). Since a negative regulation of the Mdm2 function in a cancer cell with a wild type p53 may induce apoptosis of the cancer cell, Mdm2 has been a useful target for the development of anti-cancer agent (Onel, K & Cordon-Cardo, C. Mol Cancer Res 2, 1-8, 2004). However, the apoptosis resulting from p53 stabilization through the regulation of the Mdm2 function may cause serious side effects in normal cells as well as in cancer cells, and therefore the elucidation of a pathway in cancer cells is urgently needed to regulate Mdm2 selectively.
PDLIM7 protein Enigma has PDZ and LIM domains (Bach, Mech.Dev. 91, 5-17, 2000). The LIM domain of the Enigma consists of three zinc fingers and binds with protein kinases or factors associated with insulin signaling, etc. (Kuroda et al., J. Biol. Chem., 271, 31029-31032,1996; Wu et al., J. Biol. Chem., 271, 15934-15941,1994). Furthermore, Enigma binds with Ret/ptc associated with thyroid cancer to activate it (Durick et al., Mol. Cell. Biol., 18, 2298-2308, 1998). However, Enigma's function in a cell has not been clearly understood.
The factors such as YY1, Gankyrin, Daxx, etc. are known to stabilize Mdm2 and therefore to weaken the activity of p53. The YY1 binds with both Mdm2 and p53 to thereby promote the degradation of p53, and Gankyrin enhances the enzyme activity of Mdm2 to thereby promote the degradation of p53 (Sui et al., Cell, 117,859-872,2004; Higashitsuji et al., Cancer cell, 8,75-87, 2005). While the Daxx binds with Mdm2 to stabilize Mdm2 and inhibit p53, it does not affect the self-ubiquitination activity of Mdm2 (Tang et al., Nat. Cell. Biol., 8,855-862, 2006). Mdm2 expression increases as cells proliferate (Feng et al., J. Biol. Chem., 279, 35510-35517, 2004), and however, how this occurs is not clear.
Hence, as a result of investigation on Enigma functions, the present inventors revealed a novel Mdm2-p53 regulatory mechanism which is clearly distinct from the typical regulatory factors for an Mdm2-p53 pathway in that Enigma specifically inhibits the self-ubiquitination of Mdm2 by Mdm2-dependently binding to p53, and promotes the degradation of p53 by enhancing Mdm2-dependent p53 ubiquitination. Additionally, first revealed was that the conditions of cellular proliferation, and the existence of SRF-Enigma-Mdm2 pathway in human liver cancer and stomach cancer tissues may weaken p53. Also revealed was that the Enigma overexpression in a cell increases the cell survival ability and induces its resistance to anti-cancer agents. Thus, the present invention comes to completion by revealing that p53 can be activated by inhibiting the overexpression of Enigma in cancer cells, that anti-cancer agents can be screened by selecting inhibiting factors of the Enigma-Mdm2 interaction, and that identifying the Enigma expression level in treatment with anti-cancer agents maybe used for the identification of the anti-cancer effect.